The objective of this proposal is to develop chemical techniques for the enrichment of myoglobins, hemoglobins and other proteins with 13C or alternative nuclei suitable for NMR study. The methodology is aimed at the size of molecule for which total synthesis of the polypeptide with a variety of enrichment sites is clearly impractical at the present time. The strategy, therefore, is to modify the natural protein by appropriate cleavage and resynthesis with the incorporation of the enriched amino acids by way of substitution of a fragment into the sequence. This approach has been termed semisynthesis. The chemical substitution methods will clearly serve a still broader objective, the substitution of alternative residues at given sequence positions to test structure-function relationships, to interconvert species specificity, or to redirect function. This work can be applied directly to understanding hemoglobin function and its control, and will form a basis for such broad applications as enzyme or hormone replacement therapy.